The present invention relates to a process for an optical resolution of racemic N-carbamoyl-.alpha.-amino acid by converting N-carbamoyl-.alpha.-amino acid into optically active hydantoins by a stereo-selective enzymatic reaction. According to the present invention, an optically active compound useful as a drug or a synthetic intermediate thereof can be produced with great advantage.
One of the object of the invention is to effectively produce optically active hydantoins. hydantoins of many varieties are known and many of them are used as a drug such as anticonvulsants or antipsychotic agents.
Generally, racemic hydantoins are employed. However, for improving the efficiency and reducing a side effect, using hydantoins in an optically active form is more preferable since, in many cases, only those having a particular configuration can show a physiological activity when the hydantoins have an asymmetric carbon atom.
Hitherto, the following processes have been known for preparing optically active hydantoins, i.e. (1) a process which comprises that optically active .alpha.-amino acid is reacted with an alkali metal salt of cyanic acid to give N-carbamoyl-.alpha.-amino acid, which is then heated in a mineral acid to cyclize into hydantoins,
(2) a process which comprises that cyanoacetic acid is converted into isocyanate, which is reacted with amines to give N-carbamoylaminonitryl, which is finally heated in a mineral acid to cyclize into hydantoins,
(3) a process which comprises that optically active brucine is added to racemic hydantoins to form a salt of diastereoisomer, which is subjected to an optical resolution using a difference of solubility in the solvent (J. Med. Chem. 21(12), 1294, 1978), and
(4) a process which comprises that ketone is reacted with optically active amine to give ketimine, to which hydrogen cyanide is added asymmetrically, and the resultant is reacted with chlorosulphonylisocyanate to give optically active hydantoins (J. Org. Chem. 47, 4081, 1982).
When an optically active amino acid can be obtained in a relatively easy way as in a case of natural amino acid, the process (1) is advantageous. However, when it is difficult to obtain an optically active amino acid, the process (1) and (2) usually require complicated procedures such as converting racemic compounds into acidic or basic derivatives, which is then subjected to an optical resolution, in order to obtain a starting material in an optically active form. The process (3), where racemic hydantoins are directly subjected to an optical resolution, needs brucine as a resolving agent, which has a strong toxicity, and thus this process meets many problems in the view point of workability and safety such as handling of brucine and a contamination of a product with brucine when an industrial scale production is expected. The process (4), where a desired compound in an optically active form is directly synthesized by an asymmetric synthesis, has many difficulties for practical use such as a consumption of more than an equimolar amount of expensive optically active amine and chlorosulphonyl isocyanate and a great difficulty of removal of undesired optically active portion which is derived from amine.
As the result of the inventors' extensive study on the hydantoins and N-carbamoyl-.alpha.-amino acid, which is easily obtained from the hydantions, to develop a process for efficiently synthesizing optically active hydantoins based on a biochemical technique, it has now been found that some microorganisms could produce optically active hydantoins by a stereo-selective cyclization reaction of the substrate N-carbamoyl-.alpha.-amino acid and said enzymatic reaction could be an effective means for an optical resolution, being of very wide application and effective for the production of optically active amino acid as well as an optically active hydantoins.